Method of treating inflammation utilizing alkyl esters of gallic acid

ABSTRACT

THE INVENTION PROVIDES A METHOD OF ALLEVIATING INFLAMMATION, EDEMA AND/OR PAIN IN A MAMMAL BY ADMINISTERING TO SAID MAMMAL BY THE TOPICAL ROUTE GALLIC ACID OR AN ALKYL ESTER OF GALLIC ACID, THE ALKYL MOIETY OF SAID ESTER HAVING 1 TO 8 CARBON ATOMS.

Sept. 3, 1974 S. A. SAEED ETAI- IETHOD OF TREATING INFLAIDIATIONUTILIZIHG ALKYL ESTERS 9F GALLIC ACID A Filed lay 24, 1973 United StatesPatent O 3,833,732 METHOD F TREATING INFLAMMATION UTI- LIZING ALKYLESTERS 0F GALLIC ACID Sheikh Arshad Saeed, London, and Cyril Schneider,Middlesex, England, and Barrie Maurice Phillips, Elkhart, Ind.,assignors to Miles Laboratories, Inc., Elkhart,

Filed May 24, 1973, Ser. No. 363,553 Int. Cl. A61k 27/00 U.S. Cl.424-308 4 Claims ABSTRACT OF THE DISCLOSURE The invention provides amethod of alleviating inflammation, edema and/or pain in a mammal byadministering to said mammal by the topical route gallic acid or analkyl ester of gallic acid, the alkyl moiety of said ester having 1 to 8carbon atoms.

This invention relates to the use of gallic acid and its alkyl esters inthe topical treatment of inflammation, edema and pain in mammalsincluding humans.

3,833,732 Patented Sept. 3, 1974 Propyl gallate was tested as a localanti-inflammatory agent and compared with hydrocortisone in the ratusing the method of Tonelli, Thibault and Ringler, Endocrinology, 1965,77, 625-634. It was found that propyl gallate had a significantanti-inflammatory activity having a potency of 0.03 relative tohydrocortisone; it did not, however, have the undesirable side-elfectsof the latter. The results are shown in the Table I below.

TABLE 1.-COMPARISON OF THE TOPICAL ANTIINFLAMMATORY EFFECTS OF PROPYLGALLATE AND HYDROCORTISONE Mean 5:S.D.

Increasea Percent Relative Conceu- Ear in ear inhibition potency (95%tration, Weight, weight, of ear weight confidence Compound Ing/ml. mgmg. increase limits) Propyl gallate 1 159:1:27 87. 15:27. 1 12. 05:27. 3

Do 3. 16 153:1:29 80. 55:29. 0 18. 75:29 3 l0. 0 b137:1:27 65. 35:27. 334. l5: 0. 03 31. 6 b133:1:19 (0. 01-0. 07)

Do 31. 6 b79i8 Negative control 725:4 05:5.

Positive control Calculated from negative control group average. bSignificantly (P 0.05) dilerent from positive control.

Gallic acid and its alkyl esters are known compounds (Heilbron andBunbury, Dictionary or Organic compounds, 1953, Volume 2, page 583), andcertain at least of these known compounds are known to have variouspharmacological actions in mammals, including local anesthetic activity(Modak and Rao, Indian J. Med. Res., 1971, 59, 795-8), the boosting ofthe anti-Parkinsons disease activity of L-DOPA (GermanOffenlegungsschrift 2,103,284) and bronchodilating and decongestantactivity (U.S. Patent Specification 3,639,622).

The invention provides a method of alleviating inflammation, edemaand/or pain in a mammal by applying to the mammal by the topical routegallic acid or a C1 8 alkyl ester thereof, e.g. the methyl, the ethyland particularly the propyl ester.

The method is particularly useful in the treatment of burns, for examplethose induced by ultra-violet radiation (i.e. sunburn).

The gallic acid or ester thereof can be administered in the form of apharmaceutical composition comprising it and a pharmaceuticallyacceptable carrier or diluent. The composition is preferably in a formsuitable for topical administration; examples are ointments, creams,pastes, liniments and jellies, as well as aerosol preparations.

These results are shown in graph form in the figure.

Propyl gallate also has a significant antinociceptive effect in micewhich indicates an analgesic effect in humans. The ability ofarachidonic acid to induce abdominal constrictions (writhing) in micewas significantly (P 0.01) reduced after the arachidonic acid had beenincubated at 37 C. for 25 min. with 100 11g/ml. of propyl gallate.Similar results were obtained when the arachidonic acid was replacedwithout prior incubation by acetylcholine or acetic acid. Pretreatmentof the mice with 4 mg./kg. of propyl gallate by the intraperitonealroute sigincantly (P 0.05) inhibited writhing induced by a subsequentintraperitoneal challenge with arachidonic acid; once again similarresults were obtained when the archidonic acid was replaced byacetylcholine or acetic acid. The method of Collier, Dinneen, Johnsonand Schneider, Brit. I. Pharmacol., 1968, 32, 295-310, was used in theseexperiments. The results are summarized in Table 2.

Propyl gallate does not cause abdominal constrictions in mice atconcentrations of 5 mg./ml. when injected intraparenterally, indicatinglack of irritancy when applied to the skin at these low concentrations.

Propyl gallate, and its homologues, are believed to act as free-radicalscavengers, thus indicating effectiveness in rapidly relieving pain andinflammation in humans. The speed of the local eiectiveness of acompound is basically dependent on its absorption from the vehicle whenapplied to the site of iniiammation.

TABLE 2 Inhibition by propyl gallate of abdominal constrictions(writhing) induced by araehidonie acid, acetylcholine or acetic acid inmice No. of mice responding within- Intraperitoneal N o. of treatmentmico -30 see. 0.5-2 min. 2-1() min.

AA plus control vehicle 40 4 10 22 AA plus progal (25 pgJ AA .1 35 2 5*"8 p us prog 100 ug.

mi.) 35 o *i *#2 AA min. after control vehicle 25 11 l2 N T. AA 5 min.after progal (1 mgJkg. 25 "**l *5 N T. AA 5 min. after progal (4 Ing. 20*'"O *O N.T. ACh 5 mn. after control vehicle 20 1 17 6/10 ACh 5 min.after progal (40 mgjkg.) 20 0 ***2 *1/10 Acae 5 min. after control vehee 40 0 1 19 Acae 5 min. after progal (l0 IngJkg.) 30 0 0 **3 T025 and 1mgJkg. respectively.

NOTE.-N.T.=Not tested; AA=Araeliidonie acid l mgJkg.; ACh- Aeetyleholinebromide 342 mg. base/kg.; Aeae=Acetie acid 75 mgJkgi; Progal=Propy1gallate dissolved in sodium phosphate buer, 0.05M, pH 7.0; Dose volumeswere l0 nil/kg. throughout.

4 We claim: 1. A method of treating inammaton or edema in a mammal,which method comprises:

topically administering to said mammal an effective amount of a compoundselected from the group consisting of gallic acid and an alkyl ester ofgallc acid, the alkyl moiety of said ester having 1 to 8 carbon atoms.2. A method as claimed in claim 1 in which said alkyl ester is propylgallate.

3. A method of treating inflammation associated with sunburn in amammal, which method comprises:

topically administering to said mammal an effect'ye amount of a compoundselected from the group consisting of gallic acid and an alkyl ester ofgallic acid, the alkyl moiety of said ester having 1 to 8 carbon atoms.4. A method as claimed in claim 3 in which said alkyl ester is propylgallate.

References Cited Chem. Abst. 1971, 86898 G.

STANLEY J. FRIEDMAN, Primary Examiner y Us. c1. XR. 424-311, Dig. 13

